A live-attenuated Listeria vaccine (ANZ-100) and a live-attenuated Listeria vaccine expressing mesothelin (CRS-207) for advanced cancers: phase I studies of safety and immune induction.

Abstract

PURPOSE:

Listeria monocytogenes (Lm)-based vaccines stimulate both innate and adaptive immunity. ANZ-100 is a live-attenuated Lm strain (Lm ΔactA/ΔinlB). Uptake by phagocytes in the liver results in local inflammatory responses and activation and recruitment of natural killer (NK) and T cells, in association with increased survival of mice bearing hepatic metastases. The Lm ΔactA/ΔinlB strain, engineered to express human mesothelin (CRS-207), a tumor-associated antigen expressed by a variety of tumors, induces mesothelin-specific T-cell responses against mesothelin-expressing murine tumors. These two phase I studies test ANZ-100 and CRS-207 in subjects with liver metastases and mesothelin-expressing cancers, respectively.

EXPERIMENTAL DESIGN:

A single intravenous injection of ANZ-100 was evaluated in a dose escalation study in subjects with liver metastases. Nine subjects received 1 × 10(6), 3 × 10(7), or 3 × 10(8) colony-forming units (cfu). CRS-207 was evaluated in a dose-escalation study in subjects with mesothelioma, lung, pancreatic, or ovarian cancers. Seventeen subjects received up to 4 doses of 1 × 10(8), 3 × 10(8), 1 × 10(9), or 1 × 10(10) cfu.

RESULTS:

A single infusion of ANZ-100 was well tolerated to the maximum planned dose. Adverse events included transient laboratory abnormalities and symptoms associated with cytokine release. Multiple infusions of CRS-207 were well tolerated up to 1 × 10(9) cfu, the determined maximum tolerated dose. Immune activation was observed for both ANZ-100 and CRS-207 as measured by serum cytokine/chemokine levels and NK cell activation. In the CRS-207 study, listeriolysin O and mesothelin-specific T-cell responses were detected and 37% of subjects lived ≥15 months.

CONCLUSIONS:

ANZ-100 and CRS-207 administration was safe and resulted in immune activation.

• Authors: Dung T Le, Dirk G Brockstedt, Ran Nir-Paz, Johannes Hampl, Shruti Mathur, John Nemunaitis, Daniel H Sterman, Raffit Hassan, Eric Lutz, Bentley Moyer, Martin Giedlin, Jana-Lynn Louis, Elizabeth A Sugar, Alice Pons, Andrea L Cox, Jordana Levine, Aimee Luck Murphy, Peter Illei, Thomas W Dubensky Jr, Joseph E Eiden, Elizabeth M Jaffee, Daniel A Laheru
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 3 Pg. 858-68 (Feb 01 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22147941 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Bacterial Vaccines
• Cancer Vaccines
• Cytokines
• GPI-Linked Proteins
• Msln protein, mouse
• Vaccines, Attenuated
• Mesothelin

Topics

• Adult
• Aged
• Bacterial Vaccines (administration & dosage, adverse effects, immunology)
• Cancer Vaccines (administration & dosage, adverse effects, immunology)
• Carcinoma (secondary, therapy)
• Cytokines (blood)
• Female
• Flow Cytometry
• GPI-Linked Proteins (immunology)
• Humans
• Immunohistochemistry
• Listeria monocytogenes (immunology)
• Liver Neoplasms (immunology, secondary, therapy)
• Lung Neoplasms (pathology, therapy)
• Lymphocyte Activation (immunology)
• Lymphocyte Count
• Male
• Maximum Tolerated Dose
• Mesothelin
• Mesothelioma (pathology, therapy)
• Middle Aged
• Ovarian Neoplasms (pathology, therapy)
• Pancreatic Neoplasms (pathology, therapy)
• Vaccines, Attenuated (administration & dosage, adverse effects, immunology)